Human UTY(KDM6C) is a Male-Specific Nε-Methyl Lysyl-Demethylase [Protein Structure and Folding]

May 5th, 2014 by Walport, L. J., Hopkinson, R. J., Vollmar, M., Madden, S. K., Gileadi, C., Oppermann, U., Schofield, C. J., Johansson, C.

The Jumonji C lysine demethylases (KDMs) are 2-oxoglutarate and Fe(II) dependent oxygenases. KDM6A (UTX) and KDM6B (JMJD3) are KDM6 subfamily members which catalyse demethylation of Nϵ-methylated histone 3 lysine-27 (H3K27), a mark important for transcriptional repression. Despite reports stating that UTY(KDM6C) is inactive as a KDM, we demonstrate by biochemical studies, employing mass spectrometry and NMR, that UTY(KDM6C) is an active KDM. Crystallographic analyses reveal that the UTY(KDM6C) active site is highly conserved with those of KDM6B and KDM6A. UTY(KDM6C) catalyses demethylation of H3K27 peptides in vitro, analogously to KDM6B and KDM6A, but with reduced activity, due to point substitutions involved in substrate binding. The results expand the set of human KDMs and will be of use in developing selective KDM inhibitors.